UGT1A16, UGT1A73 and UGT1A9*1b polymorphisms are predictive markers for severe toxicity in patients with metastatic gastrointestinal cancer treated with irinotecan-based regimens (original) (raw)
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Cancer Science, 2002
Irinotecan often causes unpredictably severe, occasionally fatal, toxicity involving leukopenia or diarrhea. It is converted by carboxyesterase to an active metabolite, SN-38, which is further conjugated and detoxified to SN-38-glucuronide by UDP-glucuronosyltransferase (UGT). We genotyped the UGT1A7 gene by direct sequencing analysis and polymerase chain reaction-restriction fragment length polymorphism in 118 cancer patients and 108 healthy subjects. All the patients had received irinotecan-containing chemotherapy and were evaluated to see whether the variant UGT1A7 genotype would increase the likelihood of severe toxicity of irinotecan consisting of grade 4 leukopenia and/or grade 3 or more diarrhea. Among the 26 patients with severe toxicity, the allele frequencies were 61.5% for UGT1A7 * 1, 15.4% for UGT1A7 * 2, and 23.1% for UGT1A7 * 3. On the other hand, the frequencies were 63.6% for UGT1A7 * 1, 15.8% for UGT1A7 * 2, and 20.7% for UGT1A7 * 3 among the 92 patients without severe toxicity. None of the 118 patients had UGT1A7 * 4. Neither univariate analysis (odds ratio, 1.13; 95% confidential interval, 0.46-2.75) nor multivariate logistic regression analysis (odds ratio, 0.74; 95% confidential interval, 0.26-2.07) found any significant association between carrying at least one of the variant alleles and the occurrence of severe toxicity. The distribution of UGT1A7 genotypes in 108 healthy subjects was not significantly different from that in the patients (P = = = =0.99 and 0.86 for those with and without severe toxicity, respectively), but significantly less than that in Caucasians reported previously (P < < < <0.001). The results suggested that determination of UGT1A7 genotypes would not be useful for predicting severe toxicity of irinotecan.
Cancer research, 2000
Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of the UGT1A1 would affect an interindividual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. In this case-control study, retrospective review of clinical records and determination of UGT1A1 polymorphisms were performed to investigate whether a patient with the variant UGT1A1 genotypes would be at higher risk for severe toxicity by irinotecan. All patients previously received irinotecan against cancer in university hospitals, cancer centers, or large urban hospitals in Japan. We identified 26 patients who experienced severe toxicity and 92 patients who did not. The relationship was studied between the multiple variant genotypes (UGT1A1*28 in the promoter and UGT1A1*6, UGT1A1*27, UGT1A1*29, and UGT1A1*7 in the coding region) and the severe toxicity of grade 4 leukopenia (<0.9 ؋ 10 9 /liter) and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26 patients with the severe toxicity, the genotypes of UGT1A1*28 were homozygous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 10 (11%) heterozygous were found among the 92 patients without the severe toxicity. Multivariate analysis suggested that the genotype either heterozygous or homozygous for UGT1A1*28 would be a significant risk factor for severe toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence interval, 2.52-22.3). All 3 patients heterozygous for UGT1A1*27 encountered severe toxicity. No statistical association of UGT1A1*6 with the occurrence of severe toxicity was observed. None had UGT1A1*29 or UGT1A1*7. We suggest that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients. This research warrants a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 polymorphisms prior to irinotecan chemotherapy.
Pharmacogenomics, 2009
Aims: Variants in UGT1A1 have previously been associated with toxicity from irinotecan chemotherapy. We conducted a pragmatic prospective cohort study to establish the relevance of UGT1A1 variants in the prediction of severe diarrhea and neutropenia in patients with colorectal cancer receiving irinotecan in a routine clinical setting. Materials & methods: Genotyping of UGT1A1*28 and c.-3156G>A was undertaken in an unselected, prospective cohort of 96 individuals treated with irinotecan at a single major UK oncology centre. Data on cytotoxic drugs received, and toxicity for all irinotecan treatment cycles were collected from case notes. Over 95% (92/96) of patients received an intermediate dose of irinotecan (180 mg/m2, twice weekly). Irinotecan was given in combination with other cytotoxic drugs in 93/96 subjects and Grade 3 or 4 toxicity occurred in 23% of subjects. Results: No association was found between UGT1A1*28 or c.-3156G>A and neutropenia. However, individuals carryin...
The Open Colorectal Cancer Journal, 2009
Aim: To investigate the association between UDP-glucuronosyltransferase 1A1 (UGT1A1) genotypes and severe toxicity in Taiwanese patients with metastatic colorectal cancer (mCRC) receiving irinotecan chemotherapy. Methods: We genotyped the UGT1A1 gene by direct sequencing. All the patients were evaluated to see whether the variant UGT1A1 genotype would correlate to severe toxicity of irinotecan consisting of grade III-IV neutropenia, diarrhea and nausea/vomiting. Genomic DNA was genotyped for UGT1A1, and patients were designated as 6/6, 6/7, or 7/7 depending on the number of TA repeats in the promoter region. Results: The results showed that the genotype distribution of UGT1A1 in Taiwanese subjects differed significantly from that in Caucasians. Furthermore, patients with 6/7 or 7/7 genotype were associated with a higher incidence of grade III-IV neutropenia or diarrhea or nausea/vomiting (all p < 0.0001). The less frequencies of 6/7 and 7/7 genotypes may be responsible for the considerably lower occurrence of grade III-IV neutropenia and diarrhea in Taiwanese patients. Indeed, the UGT1A1 genotype was closely related to clinical response (p = 0.018). Conclusion: UGT1A1 genotyping is a potential predictor of severe toxicity for Taiwanese mCRC patients treated with irinotecan chemotherapy, and may be useful to identify patients at-risk of toxicity, and thus could be used as a screening tool prior to therapy.
Relevance of Different UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity
Clinical Cancer Research, 2004
Purpose: We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert’s syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients. Experimental Design: Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment. Results: No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 4...
Journal of Pharmacology and Experimental Therapeutics, 2013
Background: Despite the importance of UGT1A1*28 in irinotecan pharmacogenetics, our capability to predict drug-induced severe toxicity remains limited. Objective: We aimed at identifying novel genetic markers that would improve prediction of irinotecan toxicity and response in advanced colorectal cancer patients treated with FOLFIRI-based regimens. Approach: The relationships between UGT1A candidate markers across the gene (n=21) and toxicity were prospectively evaluated in 167 patients. We included variants in the 3'UTR region of UGT1A locus, not studied in this context yet. These genetic markers were further investigated in 250 Italian FOLFIRI-treated patients. Results: Several functional UGT1A variants including UGT1A1*28 significantly influenced risk of severe hematological toxicity. As previously reported in the Italian cohort, a 5-markers risk haplotype (HII; UGTs 1A9/1A7/1A1) was associated with severe neutropenia in our cohort (OR=2.43; p=0.004). The inclusion of a 3'UTR SNP permitted refinement of the previously defined HI, in which HIa was associated with the absence of severe neutropenia in combined cohorts (OR=0.55; p=0.038). Among all tested UGT1A variations and upon multivariate analyses, no UGT1A1 SNPs remained significant, whereas three SNPs located in the central region of UGT1A were linked to neutropenia grade 3-4. Haplotype analyses of these markers with the 3'UTR SNP allowed the identification of a protective HI (OR=0.50; p=0.048) and two risk haplotypes HII and HIII, characterized by 2 and 3 unfavorable alleles respectively, revealing a dosage effect (ORs of 2.15 and 5.28; p≤0.030). Conclusions: Our results suggest that specific SNPs in UGT1A, other than UGT1A1*28, may influence irinotecan toxicity and should be considered to refine pharmacogenetic testing.
UGT1A1 polymorphism can predict hematologic toxicity in patients treated with irinotecan
2007
Irinotecan (CPT-11) is approved in metastatic colorectal cancer treatment and can cause severe toxicity. The main purpose of our study was to assess the role of different polymorphisms on the occurrence of hematologic toxicities and disease-free survival in high-risk stage III colon cancer patients receiving 5-fluorouracil (5FU) and CPT-11adjuvant chemotherapy regimen in a prospective randomized trial. Experimental Design: Four hundred patients were randomized in a phase III trial comparing LV5FU2 to LV5FU2 + CPT-11. DNA from 184 patients was extracted and genotyped to detect nucleotide polymorphism: 3435C>T for ABCB1, 6986A>G for CYP3A5, UGT1A1*28 and-3156G>A for UGT1A1. Results: Genotype frequencies were similar in both treatment arms. In the test arm, no significant difference was observed in toxicity or disease-free survival for ABCB1 and CYP3A5 polymorphisms. UGT1A1*28 homozygous patients showed more frequent severe hematologic toxicity (50%) than UGT1A1*1 homozygous patients (16.2%), P = 0.06. Moreover, patients homozygous for the mutant allele of-3156G>A UGT1A1 polymorphism showed more frequent severe hematologic toxicity (50%) than patients homozygous for wild-type allele (12.5%), P = 0.01.This toxicity occurred significantly earlier in homozygous mutant than wild-type homozygous patients (P = 0.043). In a Cox model, the hazard ratio for severe hematologic toxicity is significantly higher for patients with the A/A compared with the G/G genotype [hazard ratio, 8.4; 95% confidence interval, 1.9^37.2; P = 0.005]. Conclusions: This study supports the clinical utility of identification of UGT1A1 promoter polymorphisms before LV5FU2 + CPT-11 treatment to predict early hematologic toxicity. The-3156G>A polymorphism seems to be a better predictor than the UGT1A1 (TA) 6 TAA>(TA) 7 TAA polymorphism. Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin) (CPT-11) is a water-soluble analogue of 20(S)-camptothecin (CPT) and is an inactive prodrug. Its major metabolite, SN-38, is a potent active topoisomerase I inhibitor and is known to be toxic (1). Due to its efficacy, CPT-11 is currently approved worldwide for use as first-line therapy in metastatic colorectal cancer, in combination with 5-fluorouracil (5FU) and leucovorin (LV; ref. 2). Adjuvant CPT-11 in combination with 5FU has recently been investigated in colorectal cancer. One limitation of CPT-11 is the unpredictable and occasionally fatal gastrointestinal and hematologic toxicity, which varies greatly between individuals. Predictive markers of CPT-11 toxicity may thus be deduced from the CPT-11 metabolic pathway. CPT-11 is metabolized by carboxylesterase (CES), essentially the isoenzyme CES2, to active SN-38, then is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme to yield its h-glucuronide, SN-38 G (3, 4). SN-38 G is excreted in the small intestine via the bile, where bacterial glucuronidase breaks down the glucuronide into SN-38 and glucuronic acid (5). Bilurubin undergoes the same glucuronidation by